Glucocorticoid induces apoptosis of osteoblast cells through the activation of glycogen synthase kinase 3β

Abstract

Glucocorticoids (GCs), which play an important role in the normal regulation of bone remodeling, are widely used as anti-inflammatory and chemotherapeutic agents. However, continued exposure to GCs results in osteoporosis, which is partially due to apoptosis of osteoblasts and osteocytes. To understand the mechanism of how GCs induce cell death in osteoblasts, we examined apoptotic effects of dexamethasone (Dex), GC, on MC3T3-E1 osteoblast cells. Results revealed that Dex-induced apoptosis was inhibited by a GC receptor antagonist, mifepristone, and a general caspase inhibitor, Z-VAD-fmk, indicating that Dex induces apoptosis of MC3T3-E1 cells through the pathways involved in GC receptor and caspase. Glycogen synthase kinase 3b (GSK3b) is known to participate in apoptosis signaling in MC3T3-E1 cells. Dex activated both GSK3b and p38-mitogen-activated protein kinase (MAPK). The inhibition of GSK3b by inhibitor (LiCl) or small interference RNA (siRNA) decreased apoptosis. In contrast, the inhibition of p38-MAPK by inhibitor (SB203580) or siRNA did not decrease, but increase apoptosis. These results suggest that Dex-mediated apoptosis of osteoblasts is facilitated by GSK3b, but prevented by p38-MAPK.

Roles of osteocyte apoptosis in steroid-induced avascular necrosis of the femoral head

“…However, many questions remain concerning the pathological changes to osteocytes and osteoblasts in early SANFH and their potential causes, especially the manner in which the death of such cells is brought about and the reversible factors involved. In recent years, preliminary investigations have been performed on the role of osteocyte and osteoblast apoptosis in SANFH (Kerachian et al, 2009;Yun et al, 2009), providing a new understanding of the pathogenesis of this disease. Unfortunately, none of these studies have extensively examined the mechanism responsible for apoptosis in these two cell types.…”

Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia

“…15,16 Glucocorticoids also cause direct toxicity to osteocytes. 17 Clinical risk factors for osteonecrosis have included adolescent age between 10 and 20 years, 5,8,11,18 female sex, 11 white race, 11 and higher body mass index. 6 Some ALL treatment regimens have a much higher frequency of osteonecrosis than others, suggesting that some nonglucocorticoid drugs (eg, asparaginase and methotrexate) may modify the risk of osteonecrosis.…”

Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia

“…[36][37][38][39][40][41] Prior candidate gene and genome-wide investigations have implicated polymorphisms involved in lipid homeostasis (ACP1), fibrinolysis (SERPINE1), antifolate pharmacodynamics (thymidylate synthetase), and glucocorticoid response (VDR). 7,10,42,43 These variants did not replicate in the discovery cohort, possibly due to differences in therapy and methods of case/control ascertainment.…”